title: Increased expression of CYP24A1 correlates with advanced stages of prostate cancer and can cause resistance to vitamin D3-based therapies.
abstract: A major limitation of exogenous vitamin D3 administration for the treatment of prostate cancer is the marginal, if any, clinical efficacy. We dissected the basis for the resistance to the vitamin D3 antitumor properties and specifically examined the effect of its major catabolic enzyme, CYP24A1, in prostate cancer. Local CYP24A1 expression levels and the effect of selective modulation were analyzed using tissue microarrays from needle core biopsy specimens and xenograft-bearing mouse models. CYP24A1 mRNA was elevated in malignant human prostate tissues compared to benign lesions. High CYP24A1 protein levels were seen in poorly differentiated and highly advanced stages of prostate cancer and correlated with parallel increase in the tumor proliferation rate. The use of CYP24A1 RNAi enhanced the cytostatic effects of vitamin D3 in human prostate cancer cells. Remarkably, subcutaneous and orthotopic xenografts of prostate cancer cells harboring CYP24A1 shRNA resulted in a drastic reduction in tumor volume when mice were subjected to vitamin D3 supplementation. CYP24A1 may be a predictive marker of vitamin D3 clinical efficacy in patients with advanced prostate cancer. For those with up-regulated CYP24A1, combination therapy with RNAi targeting CYP24A1 could be considered to improve clinical responsiveness to vitamin D3.
authors.affiliation: 2Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. M.T.-L., mounia.louet@gmail.com.
authors.forename: Mounia
authors.initials: M
authors.lastname: Tannour-Louet
authors.forename: Shaye K
authors.initials: SK
authors.lastname: Lewis
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Louet
authors.forename: Julie
authors.initials: J
authors.lastname: Stewart
authors.forename: Josephine B
authors.initials: JB
authors.lastname: Addai
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.forename: Hima V
authors.initials: HV
authors.lastname: Vangapandu
authors.forename: Annisa L
authors.initials: AL
authors.lastname: Lewis
authors.forename: Kristin
authors.initials: K
authors.lastname: Dittmar
authors.forename: Robia G
authors.initials: RG
authors.lastname: Pautler
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase
keywords: RNAi; adjuvant therapy; biomarkers; xenografts